Genes encoding a new class of proteins known as cyclins have been identified as a new class of protooncogenes, and cyclin-dependent kinase (or Cdk) inhibitors have been identified as tumor suppressors, thereby uniting the molecular mechanisms of cellular transformation and tumorigenesis with the enzymology governing cell cycle control. (Hall, et al., Curr. Opin. Cell Biol., Vol. 3, pgs. 176-184 (1991); Hunter, et al., Cell, Vol. 55, pgs. 1071-1074 (1991); Hunter, et al., Cell, Vol. 79; pgs. 573-582 (1994); Elledge, et al., Curr. Opin. Cell Biol., Vol 6, pgs. 874-878 (1994); Peter, et al., Cell, Vol. 79, pgs. 181-184 (1994)). The sequential expression of specific cyclins and the essential functions of specific Cdk complexes have been defined (Wu, et al., Int. J. Oncol., Vol. 3, pgs. 859-867 (1993); Pines, et al., New Biologist, Vol. 2, pgs 389-401 (1990); Pines, Cell Growth and Differentiation, Vol. 2, pgs. 305-310 (1991); Reed, Ann. Rev. Cell Biol., Vol. 8, pgs. 529-561 (1992); Sherr, Cell, Vol. 79, pgs. 551-555 (1994)), thereby providing direct links to the fundamental mechanisms of DNA replication, transcription, repair, genetic instability, and apoptosis. (D'Urso, et al., Science, Vol. 250, pgs. 786-791 (1990); Wu, et al., Oncogene, Vol. 9, pgs 2089-2096 (1994); Roy, Cell, Vol. 79, pgs. 1093-1101 (1994); Meikrantz, et al., Proc. Nat. Acad. Sci., Vol. 91, pgs. 3754-3758 (1994)). Both the universal Cdk inhibitor p21/WAF1/CIP1 (Xiong, et al., Nature, Vol. 366, pgs. 701-704 (1993); Harper, et al., Mol. Biol. Cell, Vol. 6, pgs. 387-400 (1995)), and cyclin G1 (Wu, et al., Oncol. Reports, Vol. 1, pgs, 705-711 (1994)) are induced by the wild-type p53 tumor suppressor protein in the initiation of DNA repair and/or apoptosis. (E1-Deiry, et al., Cell, Vol. 75, pgs 817-825 (1993); E1-Deiry, et al., Cancer Res., Vol. 54, pgs. 1169-1174 (1994)). Thus, the molecular components regulating critical cell cycle checkpoints represent strategic targets for potential therapeutic intervention in the treatment of cell proliferation disorders, including pediatric bone cancers, in which the Rb and the p53 tumor suppressor genes often are inactivated. (Hansen, et al., Proc. Nat. Acad. Sci., Vol. 82, pgs. 6216-6220 (1985); Toguchida, et al., Nature, Vol. 338, pgs. 156-158 (1989); Toguchida, et al., Cancer Res., Vol. 48, pgs. 3939-3943 (1988); Diller, et al., Mol. Cell. Biol., Vol. 10, pgs. 5772-5781 (1990)). Previous studies have characterized the progressive profile of cyclin expression and Cdk activation (Wu, 1993; Carbonaro-Hall, et al., Oncogene, Vol. 8, pgs 1649-1659 (1993); Hall, et al., Oncogene, Vol. 8, pgs. 1377-1384 (1993); Williams, et al., J. Biol. Chem., Vol. 268, pgs. 8871-8880 (1993); Albers, et al., J. Biol. Chem., Vol. 268, pgs. 22825-22829 (1993)), as well as the p53-independent induction of p21/WAF1/CIP1 (Wu, et al., Oncol. Reports, Vol. 2, pgs 227-231 (1995)), in MG-63 osteosarcoma cells. Also, antisense oligonucleotide strategies directed against cyclin D1 effectively inhibit cell cycle progression in these osteosarcoma cells. (Wu, 1993).
Metastatic carcinoma is an important target for gene therapy as it is associated with poor outcome. Colorectal cancer, for example, is the second leading cause of cancer death in the United States after lung cancer, followed by breast and pancreatic cancer (Silberberg et al., Cancer Clin., Vol. 40, pgs. 9-26 (1990)). Of these carcinomas, pancreatic cancer has the worst prognosis. The median survival of patients with metastatic pancreatic cancer is three to six months and virtually all the patients are dead within a year (Merrick et al., Gastroenterol. Clin. N. Amer., Vol. 19, pgs. 935-962 (1990)). Approximately 40% of patients will have metastatic disease either to the liver or the peritoneal cavity or both at the time of diagnosis. Chemotherapy for metastatic disease is ineffective despite multimodal therapy. Hence, alternative approaches to metastatic carcinoma would be desirable.
Wu, et al. (Oncol. Reports, Vol. 1, pgs. 705-711 (1994)), hereinabove mentioned, discloses the deduced amino acid sequence and cDNA sequence for human cyclin G1 protein. Wu, et al., also disclose that higher levels of cyclin G1 expression were found in osteosarcoma cells and in Ewing's sarcoma cells than in normal diploid human fibroblasts. Although Wu, et al., state that the overexpression of cyclin G1 protein in human osteosarcoma cells provides a potential link to cancer, Wu, et al., do not disclose the treatment of cancer by interfering with or inhibiting the function of cyclin G1 protein in cancer cells.